tbuckley/cabot-search huggingface dataset:
Preliminary efficacy and safety of camrelizumab plus metronomic oral vinorelbine as first-line therapy for people aged 70 and above with advanced non-small cell lung cancer (NSCLC) from a phase II trial.
Authors: Lin Li, Ping Zhang, Jiayi Gao, Min Tang, Xin Nie, Di Ma, Zhe Zhao, Yue Yuan, Li Ding, Chao Li
Journal: Journal of Clinical Oncology (2023)

e14677 Background: Traditional platinum-based combination chemotherapy used as the standard first‐line treatment for advanced NSCLC poses potential safety risk for patients (pts) aged 70 years and above. Moreover, data on immune checkpoint inhibitors treating older pts with lung cancer in the current pivotal trials is limited. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time. Compared with traditional chemotherapy, MCT shows better safety profile and antitumor angiogenesis and immunomodulatory effects. Camrelizumab, an anti-PD-1 inhibitor, demonstrated encouraging efficacy in NSCLC (CameL study and CameL-sq study). Here, we designed a phase II trial to evaluate the efficacy and safety of camrelizumab plus metronomic oral vinorelbine (mOV) as first-line therapy for Chinese older pts with advanced NSCLC. Methods: Key inclusion factors were pts aged 70 years and above, histologically or cytologically confirmed unresectable stage III and IV NSCLC without positive EGFR mutation, ALK fusions or ROS1 fusions, ECOG performance status 0-2, no previous systematic treatment. Pts received camrelizumab (200mg, D1, q3w) combined with mOV (30mg, tiw1, day 1-3-5 per week) for 6 cycles, followed by camrelizumab monotherapy maintenance until disease progression or intolerable side effects. The primary endpoint was progression free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: From March 2021 to November 2022, 12 pts were evaluable for inclusion in the study. The median age was 77 (range: 70-85) with 8 (67%) males. Median follow-up was 7.2 months (range 2.8 months-22.1 months). The median PFS was 9.3 months (95%CI: 3.9 months-14.7 months). The one-year OS rate was 66.3%. The ORR and DCR were 50% (95%CI: 25.4%-74.6%) and 83.3% (95%CI: 50.9%-90.1%), respectively. Pts with positive or negative PD-L1 responded similarly to the treatment (respectively at 5/8 and 1/2 on ORR). The median OS and DoR have not been reached. Adverse events (AEs) with any grade were observed in 10 (83.3%) pts, of which grade III-IV AEs were observed in 2 (16.7%) pts with neutropenia and interstitial pneumonia, respectively. Immune-related adverse events (irAEs) occurred in 3 (25%) pts, of which grade III-IV irAEs occurred in one (8.3%) patient with interstitial pneumonia. No grade 5 adverse event happened. Conclusions: The regimen of camrelizumab plus mOV for the first-line therapy for older NSCLC pts showed initial promising efficacy and safety profile, which suggests it is worth further exploration. Clinical trial information: ChiCTR2100049487 .
C-reactive protein as a response biomarker to immune checkpoint blockade: A meta-analysis.
Authors: Alexander B Karol, Yu Fujiwara, Tyler J D'Ovidio, Elena Baldwin, Himanshu Joshi, Deborah Blythe Doroshow, Matt D. Galsky
Journal: Journal of Clinical Oncology (2023)

2559 Background: Tumor-promoting inflammation is a hallmark of cancer pathogenesis and is associated with poor outcomes and treatment resistance. C-reactive protein (CRP) is a routinely measured acute phase reactant whose synthesis is stimulated by cytokines and may thereby represent a surrogate for tumor promoting inflammation. Pre-treatment CRP has been associated with resistance to immune checkpoint blockade (ICB) in several studies. However, whether post-treatment changes in CRP correlate with ICB outcomes has not been systematically examined. Methods: We performed a systematic review to identify cohort studies or clinical trials in solid tumor patients receiving ICB therapy with CRP response comparator pairs (high/low) available. We included studies that had hazard ratio (HR) of overall survival (OS), progression-free survival (PFS), or odds ratio (OR) of objective response rate (ORR) available. We performed a meta-analysis using a random-effect model to evaluate if post-treatment changes in CRP are associated with ORR, PFS, or OS. Subgroup analysis for primary cancer type was performed. Heterogeneity was assessed using the I-squared statistic. Results: We screened 691 eligible studies; 19 met inclusion criteria and 2,101 patients were included. Patients experiencing post-ICB declines in CRP had improved ORR HR=4.67 [95% CI] [2.81-7.78] (p&lt;0.0001, I 2 =42%), PFS HR=2.47 [1.98-3.09] (p&lt;0.0001, I 2 =18%), and OS HR=2.28 [1.68-3.08] (p&lt;0.0001, I 2 =56%). Heterogeneity among subgroups was low in ORR (I 2 =14.6%) and PFS analysis ( I 2 =0%), and moderate in OS analysis (I 2 =64.2%). Conclusions: In patients receiving ICB therapy, post-treatment declines in CRP were associated with improved ORR, PFS, and OS across multiple histologies. These findings support the integration of on-treatment CRP decline as a clinically relevant response biomarker for novel therapies directed at modulating tumor-promoting inflammation. A meta-regression analysis will help determine optimal post-treatment CRP cutpoints. Pooled OR of ORR [95%CI] and HR [95%CI] of PFS and OS with subgroup analysis results and heterogeneity assessment. [Table: see text]
Preclinical evaluation of targeting PRAME with TCR mimic CAR T cells in AML.
Authors: Danielle Kirkey, Leila Robinson, Tiffany Hylkema, Anisha Loeb, Sommer Castro, Thao Tang, Rhonda E Ries, Cyd McKay, Christina Root, Laura Pardo, Keith Loeb, Quy Le, Soheil Meshinchi
Journal: Journal of Clinical Oncology (2023)

2553 Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment, but has had limited success against AML in part due to overlap of cell surface antigens expressed in AML and normal hematopoietic cells. To identify AML-restricted targets, we interrogated the transcriptome from over 3000 AML patients and found PRAME (Preferentially Expressed Antigen in Melanoma), an intracellular protein, to be a highly expressed AML-restricted target. Using a novel approach to target intracellular antigens, we developed a PRAME CAR T cell using a TCR mimic (mTCR) antibody, which recognizes the PRAME peptide/HLA-A2 complex on the tumor cell surface. To conduct final IND-enabling studies, we generated an in vivo patient derived xenograft (PDX) model to treat with PRAME mTCR CAR T cells. Here we demonstrate the in vivo activity of PRAME mTCR CAR T cells against a PDX AML model. Methods: We used the VL and VH sequences from the PRAME TCR mimic antibody (Pr20) to construct the single chain fragment variable domain into the 41-BB/CD3ζ CAR vector. The PDX model was derived from a PRAME + /HLA-A2 + pediatric patient with AML. PDX cells were transduced with ffluciferase for noninvasive bioluminescent IVIS imaging to monitor leukemic progression. PDX leukemia-bearing mice were treated with unmodified T-cells or PRAME mTCR CAR T cells at 5x10 6 cells (1:1 CD4:CD8) per mouse 1 week after leukemia injection. Leukemia burden was measured by IVIS imaging and peripheral blood analysis. Results: Treatment with PRAME mTCR CAR T cells led to eradication of leukemia with all mice alive &gt;100 days post-treatment, while control mice (unmodified T cells) had disease progression at Day 50 (p=0.001). Average leukemia burden in the control cohort was 3.5% at week 6 and 41.75% at week 11, while no leukemia was detected following CAR T cell treatment. In addition, the control arm had a marked expansion of leukemia with a 7.75 and 429.6 fold increase in radiance by IVIS at 6 and 11 weeks post-treatment. No significant increase in radiance was seen in the PRAME mTCR CAR T cell treated group. Human T cells (CD45+/CD3+) were detectable in the peripheral blood at Day 7 and 14 post-treatment in both the unmodified and CAR T cell treated groups. Conclusions: We demonstrate the therapeutic potential of targeting PRAME with mTCR CAR T cells in AML. We show potent efficacy with eradication of leukemia in PDX-bearing mice following treatment with PRAME mTCR CAR T cells resulting in prolonged survival. These results provide a novel approach to target PRAME with CAR T cells and provide compelling data to evaluate PRAME mTCR CAR T cells for use in clinical trials against AML. [Table: see text]
Effect of hypofractionated radiotherapy, PD-1 immunotherapy, and anti-angiogenic therapy on abscopal responses and the tumor microenvironment.
Authors: Guang Han, Zhiqiang Dong, Chunhui Li, Jianping Bi, Ding Yi, Hanping He, Wei Wei, Guoliang Pi, Ying Li, Yanping Li, Li Zhang, Vivek Verma, Desheng Hu
Journal: Journal of Clinical Oncology (2023)

e14609 Background: Hypofractionated radiotherapy (HFRT) of the primary tumor can induce abscopal effects in metastatic cancer, which could be enhanced by adding PD-1 immunotherapy (IO) and low-dose radiotherapy (LDRT) of distant disease. However, this strategy remains with suboptimal efficacy. Translational research has shown that LDRT primarily modulates the immune microenvironment of tumors in the irradiated area, a mechanism shared by anti-angiogenic therapy (AAT). Therefore, this study aimed to compare the efficacy (abscopal responses and cytokine levels in the tumor microenvironment) between HFRT+IO+AAT and HFRT+IO+LDRT. Methods: Bilateral mouse tumor models were divided into seven groups for various treatments (Table 1). After treatment, blood and tumor samples of mice were collected for analysis. We evaluated clinical effects of HFRT+IO+AAT in 4 patients with unirradiated lung metastases in a currently-accruing phase Ib study of stereotactic body radiotherapy (SBRT) plus anlotinib (AAT) with or without toripalimab (PD-1 IO) in driver mutation-negative non-small cell lung cancer (NCT05021328). Results: The results of animal studies are shown in Table 1. HFRT to the primary tumor combined with AAT and IO enhanced the abscopal response in secondary tumor compared to HFRT, HFRT+IO, HFRT+AAT, IO+AAT, as well as HFRT+LDRT+IO. The most noteworthy secondary tumor control was observed in mice receiving HFRT+IO+AAT. The enhanced abscopal responses were associated with increased infiltration of CD8+ effector T cells, increased expression of IFN-γ and levels of TNF-α. From the prospective trial population, 4 unirradiated lung lesions in the HFRT+IO+AAT cohort decreased by an average of 48% in size (n=3 partial response, n=1 stable disease). No grade 3 treatment-related toxicity was observed. Conclusions: HFRT+IO+AAT is a promising therapeutic combination that may optimize abscopal responses, potentially even further than HFRT+LDRT+IO. This new “triple therapy” was safe and efficacious in patients and deserves further study. [Table: see text]
EZH2/EZH1 inhibitor tulmimetostat (CPI-0209) in patients with advanced solid tumors or hematologic malignancies: Preliminary phase II results.
Authors: Charles Drescher, Harriet S. Walter, Thomas Gastinne, Nehal J. Lakhani, Vincent Ribrag, Drew W. Rasco, Martin Gutierrez, Ryan J. Sullivan, R. Donald Harvey, Kalyan Banda, Michal Kwiatek, Alejandro Martin Garcia-Sancho, Linda R. Duska, Pier Luigi Zinzani, Anjali Thakur, Lennart Kann, Nicola Faulhaber, Julia Jauch-Lembach, Hedy L. Kindler
Journal: Journal of Clinical Oncology (2023)

3094 Background: Many preclinical tumor models with mutations in ARID1A and BAP1 are highly sensitive to EZH2 inhibition. Tulmimetostat (CPI-0209) is an investigational oral, next-generation, dual EZH2/EZH1 inhibitor with durable target coverage. Phase I dose escalation established a recommended Phase II dose of 350 mg (Lakhani et al. ASCO 2021). We report preliminary Phase II findings from the ongoing Phase I/II study (NCT04104776). Methods: Phase II is evaluating tulmimetostat 350 mg once daily in 28-day cycles in 6 disease-based cohorts (Table). The Simon 2-stage study design requires 1 response (complete [CR] or partial [PR]) in stage 1 (n = 10 patients [pts]) for expansion to stage 2 (plus n = 19) (except in M4, see table). Primary endpoint is objective response rate (ORR) based on disease-specific criteria; secondary objectives include safety. Results: As of Nov 08, 2022, 62 pts received ≥1 dose (safety evaluable); 48 had ≥1 postbaseline tumor assessment (efficacy evaluable). Pts had median 3.2 years (0.6–19.6) since diagnosis; 77.4% had ≥2 prior lines of therapy. Cohorts M2, M5 and M6 had completed stage 1 enrollment. At cut-off, best responses among evaluable patients (Table) show 4 cohorts have at least 1 confirmed response, including 2 CR and 1 PR in 7 pts with peripheral T-cell lymphoma (PTCL). 47 pts (75.8%) experienced TEAEs leading to dose modifications, 20 (32.3%) had serious TEAEs, and 5 (8.1%) discontinued treatment due to TEAEs. The most frequent TEAEs (≥15% of pts) (any Grade/Grade ≥3) considered at least possibly related to tulmimetostat were thrombocytopenia (51.6%/27.4%), diarrhea (45.2%/12.9%), nausea (37.1%/0%), anemia (30.6%/16.1%), fatigue (29.0%/0%), alopecia (25.8%/1.6%), dysgeusia (24.2%/0%), vomiting (21.0%/0%), and neutropenia (17.7%/14.5%). Conclusions: Based on response criteria of ORR ≥1/10 pts, the ovarian (M2), endometrial (M3), and mesothelioma (M5) cohorts achieved eligibility for stage 2 expansion (not relevant in M4). The safety profile of tulmimetostat is consistent with EZH2 inhibition and previous data. These preliminary findings in heavily pretreated pts with multiple tumor types, including tumors with ARID1A alterations or BAP1 loss, support ongoing investigation of tulmimetostat. Clinical trial information: NCT04104776 . [Table: see text]
Safety and efficacy of tumor treating fields (TTFields) prior and concomitant to radiotherapy in patients with newly diagnosed glioblastoma: Results from PriCoTTF.
Authors: Seid Kebir, Lazaros Lazaridis, Teresa Schmidt, Christoph Oster, Martin Proescholdt, Peter Hau, Anca L. Grosu, Dietmar Krex, Ulrich Sure, Björn Scheffler, Christoph Kleinschnitz, Christoph Pöttgen, Martin Stuschke, Martin Glas
Journal: Journal of Clinical Oncology (2023)

2050 Background: Tumor Treating Fields (TTFields) therapy is a locoregional, antimitotic cancer modality that utilizes electric fields delivered noninvasively to the tumor region using arrays. Preclinical findings have demonstrated that TTFields have an enhanced inhibitory effect on glioblastoma (GBM) cell proliferation when used concomitantly with radiotherapy (RT). These results provided the rationale for the phase 1/2 PriCoTTF study that investigated the safety and efficacy of TTFields therapy initiated prior and concomitant to radio-chemotherapy in adult patients with newly diagnosed (nd)GBM. Methods: TTFields therapy was initiated following surgery and continued concomitant with radio-chemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was permitted upon GBM recurrence. RT was conducted with arrays placed on the patients’ scalp. The primary endpoint was safety and tolerability gauged by a series of pre-selected treatment-limiting toxicities (TLTs). Results: The baseline characteristics of 33 patients enrolled to date were typical for GBM, except for a small proportion of patients with gross total resection (22.5%). The frequency of adverse events (AEs) grade ≥ 3 was comparable to other studies in GBM. Of note, grade ≥ 3 skin AEs only occurred in 2 patients (6%) and no patients developed a TLT. The median duration of TTFields therapy was 8.4 months. Median overall survival (OS) was not reached (48% of events had occurred), which precluded conclusions regarding efficacy. However, notably, multivariable Cox regression found that OS was independently associated with the number of days patients achieved &gt; 23 h TTFields therapy (HR 0.96, 95% CI 0.93–0.99, P = 0.008). Conclusions: The PriCoTTF study met its primary endpoint by finding that TTFields therapy concomitant with RT was well tolerated in patients with ndGBM. This included that high-grade skin toxicities were rare. Longer follow up is needed to estimate the efficacy of TTFields therapy in this setting, and will need to consider the relatively low overall duration of TTFields therapy and proportion of patients who received GTR.
Artificial intelligence (AI) –powered spatial analysis of macrophages in tumor microenvironment and its association with interferon-gamma (IFNG) signature and immune phenotype (IP) in pan-cancer dataset.
Authors: Chiyoon Oum, Gahee Park, Heon Song, Jinhee Lee, Sergio Pereira, Sanghoon Song, Sukjun Kim, Wonkyung Jung, Chan-Young Ock
Journal: Journal of Clinical Oncology (2023)

2621 Background: Macrophages are known to play a crucial role in cancer progression, but few studies have reported macrophage spatial distribution and its association with genomic signatures and tumor-infiltrating lymphocytes (TIL). Here, we applied an AI-powered Whole Slide Image (WSI) analyzer in The Cancer Genome Atlas (TCGA) pan-cancer dataset to show correlation between specific localization of macrophage and anti-tumor activity, which is reflected by IFNG signature and IP based on spatial TIL density. Methods: For spatial macrophage analysis in TCGA pan-cancer dataset, we used Lunit SCOPE IO, an AI-powered H&amp;E WSI analyzer, which identifies and quantifies various classes of cells such as tumor cell, macrophage, and TIL within cancer or stroma area. IPs were defined as follows: inflamed IP (IIP) as high intratumoral TIL (iTIL) and stromal TIL (sTIL); immune-excluded IP (IEP) as low iTIL and high sTIL; immune-desert IP (IDP) as low TIL overall. The immune cell profiling and quantification of the IFNG signature score were analyzed by using CIBERSORT and RSEM. Results: In TCGA dataset (N = 7,402), median macrophage density in total TME area (tMP) was 19.9 /mm2 (interquartile range [IQR] 9.0-44.9), and it was highly enriched in lung adenocarcinoma (median 65.1, IQR 34.3-110.0), lung squamous cell carcinoma (61, 32.4-101.3), and head and neck squamous cell carcinoma (39.4, 19.6-77.3). Based on IP classification, tMP was highly enriched in IIP (37.8, 18.7-73.8) compared to IEP (25.5, 13.8-48.6) and IDP (8.9, 4.4-17.1). Interestingly, spatial analysis showed that intratumoral macrophage density (iMP) in IIP was highly enriched compared to the others (mean fold change 2.57) and the difference of stromal macrophage density (sMP) among IPs was relatively smaller (mean fold change x1.85). Classified into four groups based on median values of iMP and sMP, high-iMP/high-sMP group had the highest proportion of IIP (47.3% vs 18.7%, p &lt; 0.001), whereas low-iMP/high-sMP group had the highest one of IEP (54.9% vs 32.3%, p &lt; 0.001) compared to the others, respectively. Moreover, the high-iMP/high-sMP group had the highest level of IFNG signature score among 4 groups (x2.13 times higher, p &lt; 0.001). Notably, both iMP and sMP were significantly correlated with CD68 expression (rho 0.292 and 0.287) but CSF1R expression was more strongly correlated with iMP (rho 0.259) compared to sMP (rho 0.078). Conclusions: IIP, IFNG signature, and CSF1R expression are more strongly correlated with intratumoral macrophage density versus stromal macrophage density, suggesting a relationship between macrophage location and function in the TME warranting further investigation.
Uliledlimab and toripalimab combination therapy in treatment naive advanced NSCLC: Phase 1b/2 clinical trial results using CD73 as a potential predictive biomarker.
Authors: Qing Zhou, Lin Wu, Bo Jiang, Yingying Du, Buhai Wang, Xiaohua Hu, Yong He, Mingfang Zhao, Yu Yao, Jiuwei Cui, Xiaorong Dong, Haibo Zhang, Rui Ma, Huijuan Wang, Jian Zhang, Jinjing Xia, Yanni Zhang, John W. Hayslip, Andrew X. Zhu, Yi-Long Wu
Journal: Journal of Clinical Oncology (2023)

2570 Background: CD73 is a rate-limiting enzyme in adenosine pathway promoting immune suppression in tumor microenvironment. The role of CD73 as a novel target in cancer immune therapy is further supported by correlation between its high expression in tumors and poor prognosis in cancer pts. Here we evaluate safety and efficacy of uliledlimab, a differentiated CD73 antibody, in combination with toripalimab, a PD-1 antibody, in treatment naive NSCLC pts. In particular, we investigate the correlation between clinical response and tumor CD73 expression to assess its value as a potential predictive biomarker, following a previous study where a correlation was indicated (Robert F, et al. ASCO 2021). Methods: Pts with treatment naïve advanced NSCLC (EGFR/ALK wild type) were enrolled in a dose-expansion cohort and received uliledlimab (20mg/kg or 30mg/kg Q3W) in combination with toripalimab 240mg Q3W. Safety, the primary endpoint, and clinical efficacy including ORR, determined by iRECIST, were evaluated. Baseline CD73 and PD-L1 expression in tumor specimens were measured by IHC. The cut-off value for CD73 High expression was assessed by ROC analysis for correlation with ORR. Results: As of 12/2/22, 66 pts were enrolled (median age 62.5 years, ECOG PS 0 40.6%, male 84.8% and never smokers 22.7%) and received at least one dose. Treatment-related adverse events (TRAEs) occurred in 86.4% of pts (Gr≥3, 15.2%) with no grade 5 TRAE. One patient was discontinued due to TRAE (1.5%). Efficacy was analyzed in 48 pts who were enrolled at least 90 days prior to data cut-off, allowing for two assessments. Baseline PD-L1 and CD73 expression was available in 45 pts. 40% of tumor or immune cells with ≥1+ staining intensity by IHC was determined as a preliminary cut-off for CD73 High (the area under ROC curve =0.72, p = 0.02). While ORR and DCR were 31.3% (15/48) and 79.2% (38/48) respectively in all pts, ORR appeared higher in CD73 High pts (50%, 9/18) and much lower in CD73 Low pts (14.8%, 4/27). Highest ORR was found in a cohort with CD73 High and PD-L1 TPS≥1% (57.1%, 8/14). Conclusions: Uliledlimab and toripalimab combination therapy was well-tolerated in treatment naïve advanced NSCLC pts. Clinical response of the therapy seems to correlate with high tumor CD73 expression, indicating a potential value of CD73 as a predictive biomarker. The study warrants a biomarker-guided randomized clinical trial that is currently in preparation. Clinical trial information: NCT04322006 .